Chemical compounds and processes of preparing the same



United States Patent CHEMICAL COMPOUNDS AND PROCESSES OF PREPARING THESAME Martin Seidman, Chicago, 111., and Karl Paul Link, Middleton, Wis.,assignors to Wisconsin Alumni Research Foundation, Madison, Wis., acorporation of Wisconsin No Drawing. Application March 2, 1953, SerialNo. 339,938

Claims. (Cl. 260-343.2)

The present invention relates to new chemical compounds and processes ofpreparing the same. More specifically, the present invention is directedto 3,4-substituted coumarins and improved processes of preparing thesame. The products of the present invention are of interest in theanticoagulant field generally and the rodenticide field specifically,and may be used as intermediates for the preparation of other products.

Shortly after the anticoagulant 3,3-methylenebis l-hydroxycoumarin) wasisolated from spoiled sweet clover hay, identified, and synthesized, itsmarked toxicity in the rat was noted. H. S. Overman, I. B. Field, C. A.Baumann, and K. P. Link, 1. Nutrition, 23, 589 (1942); K. P. Link,Harvey Lecture Series, 39, 162( 1943-44). The results of a recent surveyin the rodenticide field have shown that 3 (u-acetonylbenzyl) 4hydroxycoumarin, known in the art as warfarin, is approximately fiftytimes more lethal and in addition the time to elfect kill is about halfthat required by 3,3-methylenebis (4-hydroxycoumarin).

The products of the present invention are cyclic ketals and specially2-methyl-2-oxy 4 phenyl 5 oxodihydropyrano (3,2-c) (1) benzopyran. Theoxy groups at the 2-position are characterized by a hydrocarbon radicalwith double carbon to carbon bonds.

The following examples will serve to illustrate the present invention:

EXAMPLE I 2 methyl-2-benzyl0xy-4-phenyl 5 oxodihydropyrano (3,2-c) (1)benzopyran.A suspension of g. of warfarin in 100 ml. of benzyl alcoholwas treated with hydrogen chloride until solution resulted(approximately three minutes). After standing overnight at roomtemperature the solution was poured into 600 ml. of ice water giving anoil. The water layer was removed by decantation and 100 ml. of methanolwas added. The solution was refrigerated for five days and the solidwhich had formed had a melting point of l48l52 C. Afterrecrystallization from absolute ethanol for analysis the melting pointwas raised to l62l63 C. The filtrate from the above was returned to therefrigerator and more crystals appeared. These had a melting point of123- 140 C. and were a mixture of diastereomeric racemates.

EXAMPLE II Z-methyl-Z-allyloxy 4 phenyl 5 oxodihydropyrano (3,2-c) (1)benz0pyran.Hydrogen chloride was bubbled into a suspension of 5 g. ofwarfarin in 50 ml. of allyl alcohol until a clear solution resulted.After standing at room temperature for three hours the mixture waspoured into 500 ml. of ice and Water with stirring. A gum formed whichwas dissolved in 30 ml. of boiling methanol. Upon cooling crystals witha melting point of ll5140 C. appeared. Water was then added cautiouslyto the mother liquor until a faint turbidity was induced. Upon furthercooling more product crystallized out. By repeated recrystallization ofthis more soluble fraction 2. pure racemate, melting point l21.5l23 C.was obtained.

In the above examples the 2-oxy group is a 2-(OCH2R') group where R isselected from the group consisting of Cal-I5 (phenyl) and CH=CH2.

The improved process of the present invention has been found to beparticularly adaptable for preparing cyclic ketals in high yields. Itwas discovered, for example, that the presence of excess HCl did notdisturb the reaction, i. e. that it was not necessary to employ astandardind 4% alcoholic HCI as called for in the Stahmann et al. Patent2,427,579. This discovery made it possible to simplify the overallprocedure materially in commercial operations. Also, as it wasdiscovered that the reaction mixture gave oft heat as the gaseous HClwas bubbled into the reaction mixture in accordance with the presentinvention, it was found that it was not necessary to reflux withexternal heat to speed up the reaction. This characteristic which makesit possible to avoid the expense of applying heat together with thecharacteristic noted above which makes it possible to avoid the troubleand expense of standardized solutions, coupled with the high yieldsobtained, makes the process of the present invention a distinctimprovement, particularly in large scale commercial operations, over theprocess of the Stahmann et a1. patent.

In addition to the reactions with aralkyl alcohols (benzyl alcohol) andunsaturated aliphatic alcohols (allyl alcohol) described in the aboveexamples, the reaction may be carried out with warfarin and varioustypes of alcohols providing the alcohols have an available hydroxylgroup and are liquid at room temperature. The reactions carried out withethylene glycol monoethylether and tetrahydrofurfuryl alcohol, both ofwhich are described and claimed in our copending application Serial No.213,485, filed March 1, 1951, now Patent No. 2,665,281, arerepresentative examples. The reaction may also be carried out with thelower aliphatic alcohols such as methyl, ethyl, propyl, etc. liquidalcohols. The following example is illustrative.

EXAMPLE III 2-methyl-2-meth0xy 4 phenyl 5 oxodihydropyrano (3,2-c)(1)benzopyran.Sixty grams of warfarin was suspended in 300 ml. ofmethanol and hydrogen chloride passed in. The mixture became warm and aclear solution resulted. A mass of crystals then appeared. After coolingthe product was filtered off and washed with methanol and dilute sodiumhydroxide solution. The mother liquor and the washings were then pouredinto an excess of water and the solid which precipitated was filteredolf. The combined precipitates were recrystallized from benzene, andgave 59 g. of the desired product, melting point l63l64 C. This is ayield which is substantially higher than the previously reported yieldof 83 employing the old process.

Warfarin possesses an asymmetric carbon atom and the form used in theabove reactions was the DL racemate. Since the synthesis of the cyclicketals results in the formation of a second asymmetric carbon atom twodiastereoisomeric racemates should be formed. The products were allobtained in very good yield as mixtures of isomers.

The present application is a continuation-in-part of our applicationSerial No. 213,485, filed March 1, 1951, now Patent No. 2,665,281.

We claim:

1. The product,2-methyl-2-(OCHzR')-4-phenyl-5-oxodihydropyrano(3,2-c)(l) benzopyran,where R' is a hydrocarbon radical with a double carbon to carbon bondselected from the group consisting of phenyl and CH=CH2.

2. The product, 2-methyl-2-benzyloxy-4-phenyl-5-oxodihydropyrano(3,2-c)(1) benzopyran.

3. The product,Z-methyl-2-allyloxy-4-phenyl-5-oxodihydropyrano(3,2-c) 1) benzopyran.

4. The process of preparing cyclic ketals which comprises bubblinggaseous hydrogen chloride at room temperature into a suspension ofwarfarin in an alcohol which is liquid at room temperature until thewarfarin goes into solution, pouring the resulting reaction mixturecontaining the cyclic ketal into cold water, separating the impurereaction product from the resulting aqueous mixture and purifying thereaction product by crystallization froman organic solvent.

5. The process of claim 4 where the alcohol is methyl alcohol.

References Cited in the file of this patent UNITED STATES PATENTSStahmann et a1. Sept. 16, 1947

1. THE PRODUCT,2-,ETHYL-2-(COH2R'')-4-PHENYL-5-OXODIHYDRROPYRANO(3,2-C)(1) BENZOPYRAN,WHERE R'' IS A HYDROCARBON RADICAL WITH A DOUBLE CARBON TO CARBON BONDSELECTED FROM THE GROUP CONSISTING OF PHENYL AND CH=CH2.